The proposed studies will investigate the actions of insulin and IGF-1 and their respective receptors in the CNS of normal animals and the insulin resistant, obese fa/fa Zucker rat. The goals are to add to existing knowledge on the location of the receptors for insulin and IGF-1, the mechanisms by which they provide biological signals, and whether circulating insulin can activate the CNS insulin receptor. A final goal is to determine if an abnormality exists in any of the signalling activities of the insulin receptor of insulin resistant Zucker rats. The specific aims are to: 1. Determine the locations of insulin and IGF-1 receptors at the cellular and ultrastructural levels by immunocytochemistry and correlate the findings with the location of phosphotyrosine containing proteins. 2. Characterize the structural features of the IGF-1 receptor and evaluate the effects of tyrosine kinase activities of the insulin and IGF-1 receptors on endogenous substrates and on potential receptor signaling mechanisms. 3. Investigate the ability of circulating insulin to elicit a response in the CNS. 4. Evaluate whether the actions of insulin are altered in the CNS of insulin resistant, obese (fa/fa)Zucker rats. These specific aims will test the following hypotheses: i.Insulin receptors and IGF-I receptors are located in different neuronal populations. ii.Two isoforms exist for the beta subunit of the IGF-I receptor which can generate a hybrid receptor. iii.Both receptors signal via tyrosine kinase activity to enhance the tyrosine phosphorylation of endogenous substrates and PtdIns-3 kinase (type 1). iv.Circulating insulin can directly activate the CNS insulin-receptor. v. The insulin resistance of obese Zucker rats is associated with a defect in the tyrosine kinase signaling pathway for the CNS insulin receptor. The long-term goal of this work is to understand the roles for insulin and IGF-I in the regulation of CNS function.